Getting to the Bottom of Treatment: An Update in the Management of Esophagogastric Cancers

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1 Getting to the Bottom of Treatment: An Update in the Management of Esophagogastric Cancers Disclosures None Cindy L. O Bryant, PharmD, BCOP, FCCP, FHOPA Professor, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences Learning Objectives Describe the current use of chemotherapy and radiation in the treatment of esophagogastric cancers Interpret the use of targeted therapies and immunotherapy in the management of esophagogastric cancers Evaluate supportive care and survivorship interventions for patients with esophagogastric cancers Incidence of Esophagogastric Cancers Esophageal & Esophagogastric Junction (EGJ) Cancers US estimations for 2018 New cases 17,290 Deaths 15,850 More common Men > women > older age, heavy alcohol use, tobacco use Median age of diagnosis 68-years old Median 5-year survival 19.2% US estimations for 2018 New cases 26,240 Deaths 10,800 More common Men > women > in other races and ethnicities that non- Hispanic whites Median age of diagnosis 68-years old Median 5-year survival 31% SEER Anatomy and Pathology Esophageal & EGJ Cancers Squamous cell (<30%) Commonly found in the upper and middle part of the esophagus Adenocarcinoma Most often found in the lower third of the esophagus Anatomy and Pathology Adenocarcinoma Diffuse Less differentiated Occurs in proximal stomach Intestinal More differentiated Occurs in distal stomach Rice TW et al. J Thor Oncol Page MR and Patel S. AMJC: Evidenced-Based Oncology June

2 Risk Factors Esophageal & EGJ Cancers Squamous cell (<30%) Smoking and alcohol Hereditary syndromes Adenocarcinoma Obesity/ BMI GERD Barrett s esophagus Adenocarcinoma Diet High salt intake and salt-preserved food High nitrate consumption Smoking H. Pylori infection Genetic syndromes Clinical Presentation Esophageal & EGJ Cancers Dysphagia Weight loss Odynophagia Anemia Hoarseness Aspiration pneumonia Early stage Stomach discomfort Bloated feeling after eating Nausea Loss of appetite Heartburn Advanced stage Blood in stool Vomiting Weight loss Stomach pain Jaundice Ascites Surgical Intervention Esophageal & EGJ Cancers Medically fit for surgery Stage 0-I Endoscopic therapies (preferred) Endoscopic resection + ablation Ablation Esophagectomy Stage II-III Esophagectomy (low risk disease) Non-surgical candidate Stage 0-I Endoscopic resection + ablation Ablation Medically fit for surgery Stage 0-I Endoscopic resection Gastrectomy National Comprehensive Cancer Network (NCCN) Esophageal and Esophagogastric Cancers v2.2018; NCCN Gastric Cancer v Stage Primary Treatment Option Esophageal & EGJ Esophageal & EGJ Gastric Squamous cell Adenocarcinoma Adenocarcinoma Medically fit II-III Preoperative chemoradiation Preoperative chemoradiation Perioperative (non-cervical) (category 1) chemotherapy (category 1) Definitive chemoradiation Definitive chemoradiation Preoperative (only for patient who declines (only for patient who declines chemoradiation surgery; recommended for surgery) cervical) Perioperative chemotherapy (thoracic) Preoperative chemotherapy (thoracic) IVa Definitive chemoradiation Definitive chemoradiation Perioperative Chemotherapy (invasion to Chemotherapy (invasion to chemotherapy (category 1) trachea, great vessels or trachea, great vessels or Preoperative heart) heart) chemoradiation Non-surgical II-IVa Definitive chemoradiation Definitive chemoradiation Chemoradiation (able to tolerate treatment) (able to tolerate treatment) Chemotherapy Palliative RT or best Palliative RT or best Palliative management supportive care (unable to supportive care (unable to tolerate treatment) tolerate treatment) Preoperative and perioperative chemotherapy Regimen Overall survival (OS) 5-year OS Pathological Complete Regression Preoperative (Adenocarcinomas of the thoracic esophagus & EGJ only) OEO2 1, months vs. 23% vs. 17.1% _ Cisplatin + 5-FU vs. surgery 13.3 months OEO months vs. 42% vs. 39% _ ECX vs. Cisplatin + 5-FU 23.4 months (3-year OS) Perioperative (Esophageal, EGJ and Gastric Cancers) MAGIC 4 NR 36.3% vs. 23% _ ECF vs. surgery AIO-FLOT 5 16% vs. 6% FLOT vs. ECF FNCLCC ACCORD 6 NR 38% vs. 24% _ Cisplatin + 5-FU vs. surgery Regimens Preoperative Chemotherapy 2 cycles Recommended regimen Cisplatin + 5-FU (Category 2B) Perioperative Chemotherapy 3 cycles pre- & post-operative Preferred regimens 5-FU + oxaliplatin (category 2A) 5-FU, leucovorin, oxaliplatin, docetaxel (FLOT) (category 1) Other recommended regimen Cisplatin + 5-FU (category 1) ECX - epirubicin, capecitabine, oxaliplatin; ECF epirubicin, cisplatin, 5-FU; FLOT- 5-FU, leucovorin, oxaliplatin, docetaxel 1. Medical Research Council Oesophageal Cancer Working Group. Lancet 2002.; 2. Allum WH et al. J Clin Oncol 2009.; 3. Anderson D et al. J Clin Oncol 2015.; 4 Cunningham D et al. N Eng J Med 2006.; 5. Al-Batran SE et al. Lancet Oncol 2016.; 6. Ychou M et al. J Clin Oncol

3 Preoperative chemoradiation CROSS trial Randomized, Phase III trial in resectable esophageal or EGJ cancer N = 368 Surgery alone vs. carboplatin + paclitaxel + concurrent radiation followed by surgery Primary endpoint: Overall survival (OS) Results Median OS 49.4 months in the chemoradiotherapy surgery group vs months in the surgery group (HR 0.657; 95% CI to 0.871; P=0.003) Complete resection (R0) achieved in 92% of patients in the chemoradiotherapy surgery group vs. 69% in the surgery group (P<0.001) Most common side effects in the chemoradiotherapy-surgery group were leukopenia, neutropenia, anorexia and fatigue Preoperative Chemoradiation Preferred regimens Carboplatin + paclitaxel (category 1) 5-FU + oxaliplatin* (category 1) Other recommended regimens Cisplatin + 5-FU (category 1) Paclitaxel + fluoropyrimidine (5-FU or capecitabine) (category 2B) Irinotecan + cisplatin (category 2B) (esophageal & EGJ cancers only) *Infusional 5-FU can be replaced with capecitabine Van Hagen P et al. N Engl J Med Postoperative management Has not received preoperative chemoradiation or chemotherapy R0 resection R1 resection R2 resection Surveillance Chemoradiation (5-FU-based)* Chemoradiation (5-FU-based) Chemoradiation (5-FU-based) Palliative management *Esophageal, EGJ and gastric adenocarcinoma only Postoperative chemoradiation SWOG9008/INT-0116 Randomized, Phase III trial in resectable EGJ or stomach cancer N = 566 Surgery alone vs. surgery + postoperative chemoradiation with bolus 5-FU and leucovorin before, during, and after radiotherapy Primary endpoint: Overall survival (OS) Results Median OS 36 months in the postoperative chemoradiation arm vs. 27 months in the surgery arm (HR 1.35; 95% CI 1.09 to 1.66; P=0.005) 3-year OS 50% months in the postoperative chemoradiation arm vs. 41% in the surgery arm Dosing associated with increased rates of grade 3-4 toxicities Regimen is not recommended by NCCN Infusional 5-FU and leucovorin or capecitabine recommended MacDonald JS et al. N Engl J Med Postoperative management Has received preoperative chemoradiation or chemotherapy R0 resection R1 resection R2 resection Surveillance Chemotherapy (if receive preoperatively) Chemoradiation (5-FU-based)* Surveillance Chemoradiation (5-FU-based) Chemotherapy (if receive preoperatively) # Consider re-resection^ Surveillance Chemoradiation (5-FU-based)^ Palliative management Esophageal & EGJ Cancers Definitive chemoradiation RTOG ,2 Chemoradiation with Cisplatin + 5-FU vs. radiation alone N = 121 Primary endpoint: OS Results Median OS 14 months in chemoradiation arm vs. 9 months in radiation alone arm 5-year OS 27% in chemoradiation arm vs. 0% in radiation alone arm PRODIGE5/ACCORD17 3 Chemoradiation + FOLFOX vs. Cisplatin + 5-FU N = 134 Primary endpoint: Progression-free survival (PFS) Results Median PFS 9.7 months in FOLFOX arm vs. 9.4 months in 5-FU + cisplatin arm FOLFOX a more convenient option *Esophageal & EGJ adenocarcinoma only; #Gastric cancer only; ^Esophageal, EGJ and gastric adenocarcinoma 1. Herskovic A et al. N Eng J Med. 1992; 2. Copper JS et al. JAMA. 1999; 3. Conroy T et al Lancet Oncol

4 Definitive Chemoradiation Preferred regimens Cisplatin + 5-FU (category 1) 5-FU + oxaliplatin* (category 1) Paclitaxel + carboplatin (category 2A) Other recommended regimens Cisplatin + docetaxel or paclitaxel (category 2A) Irinotecan + cisplatin (category 2B) Paclitaxel + fluoropyrimidine (5-FU or capecitabine) (category 2B) *Infusional 5-FU can be replaced with capecitabine Supportive Care Issues in Early Stage Cancer Smoking cessation Nutritional support Adequate hydration and caloric intake Feeding tubes Jejunostomy > gastrostomy Anti-emetics appropriate for treatment regimen ph altering medications Side effect management Mucositis Diarrhea Neuropathy Pain management NCCN Esophageal and Esophagogastric Junction Cancer v Survivorship Care General Routine surveillance Annual history and physical Maintain healthy lifestyle Healthy body weight Physical activity Healthy diet Limit alcohol consumption Smoking cessation Immunizations Cancer screening Survivorship Care Management of long-term sequelae Malnutrition/Malabsorption Weight loss Vitamin deficiencies Vit B12, Vit D, Calcium, Iron Delayed gastric emptying Dumping syndrome Diarrhea Nausea Indigestion ph altering medications Blood pressure and blood glucose issues (esophageal cancers) Chemotherapy-induced neuropathy Radiation-induced cardiotoxicity (esophageal cancers) Fatigue Bone health Unresectable locally advanced, Locally recurrent or Metastatic disease Karnofsky PS > 60% or ECOG PS < 2 Karnofsky PS < 60% or ECOG PS > 3 Systemic therapy and/or Palliative/Best supportive care Palliative/Best supportive care First-line Chemotherapy Preferred Regimen CF 1 (category 1) Cisplatin mg/m 2 IV D1 5-FU mg/m 2 CIV D1-4 every 28 days XP 2 (category 1) Cisplatin 80 mg/m 2 IV D1 Capecitabine 1000 mg/m 2 PO BID on D1-14 every 21 days FOLFOX 3 Oxaliplatin 85 mg/m 2 IV D1 Leucovorin 400 mg/m 2 IV D1 5-FU 400 mg/m 2 IV D1 5-FU 1200 mg/m 2 CIV D1&2 every 14 days CapeOx 4 Oxaliplatin 130 mg/m 2 IV D1 Capecitabine 1000 mg/m 2 PO BID on D1-14 every 21 days * TTP - time to progression Response Rate TTP/PFS OS 35% n/a 8.3 months 41% 5.6 months 10.5 months 41% 5.6 months 10.7 months 44% 12.4 months 13.3 months 1. Bleiberg H et al. Eur J Cancer Al Batran SE et al. J Clin Oncol Kang YK et al. Ann Oncol Kim GM et al. Eur J Cancer

5 Event First-line Chemotherapy Regimen Other Recommended DCF 1 Docetaxel 75 mg/m 2 D1 Cisplatin 75 mg/m2 D1 5-FU 750 mg/m 2 CIV D1-5 every 21 days ECF 2 Epirubicin 50 mg/m 2 D1 Cisplatin 60 mg/m 2 D1 5-FU 200 mg/m 2 /d CIV D1 21 every 21 days Carbo/paclitaxel 3 Carboplatin AUC 5 IV D1 Paclitaxel 200 mg/m 2 IV D1 every 21 days FOLFIRI 4 Irinotecan 180 mg/m 2 Lecovorin 400 mg/m 2 5-FU 400 mg/m 2 bolus followed by 2400 mg/m 2 CIV every 2 weeks Response Rate TTP/PFS OS 37% 5.6 months 9.2 months 42% 7.0 months 9.4 months 33% 4.9 months 7.5 months 39% 5.3 months 9.5 months Biomarkers Human epidermal growth factor receptor (HER2) Esophagogastric cancers Positivity varies from 2-45% Adenocarcinoma > Squamous Gastric cancer Positivity varies from12-23% Intestinal > Diffuse Prognostic significance unclear Testing recommended in metastatic disease * TTP - time to progression 1. Van Cutsem E et al. J Clin Oncol Ross P et al. J Clin Oncol Gadgeel SM et al. Am J Clin Oncol Guimbaud R et al. J Clin Oncol ToGA Trial HER2-positive advanced GC (N = 594) Stratified Advanced vs metastatic GC vs GEJ cancer Measurable vs non-measurable ECOG PS 0 1 vs 2 Capecitabine vs 5FU 5FU or Capecitabine* a + cisplatin (n = 290) 5FU or Capecitabine a + cisplatin + trastuzumab (n = 294) a Chosen at investigator s discretion. Phase III, randomized, open-label, international, multi-center study 3807 screened ; 810 (22.1%) HER2-positive Primary end point: OS ToGA Primary Endpoint: Overall Survival Time (months) FC FC + T FC + T n = 294 FC n = 290 Events, no Median OS, mos HR = 0.74 (95% CI, ) P=0.046 Benefit limited to patients with IHC 3+ or IHC 2+ and FISH positivity OS 16 months FC + T vs months FC Bang YJ et al. Lancet FC - 5FU or capecitabine + cisplatin; T - trastuzumab. Bang YJ et al. Lancet First-line Treatment Targeted Therapy HER2-positive disease Trastuzumab should be added to first-line chemotherapy for HER2 overexpressing metastatic adenocarcinomas It is not recommended for use with anthracyclines Biomarkers Deficient mismatch repair/microsatellite instability-high (dmmr/msi-h) Site-agnostic indication Testing recommended in metastatic disease Programmed death-ligand 1 (PD-L1) Testing recommended in metastatic disease Pembrolizumab Recurrent, locally advanced, metastatic EGJ cancer Gastric cancer Tumors with CPS > 1 Third or subsequent-line of treatment Epstein-Bar Virsus (EBV) Gastric cancer Testing not recommended at this time 5

6 Overall survival probability -currents-blog/2017/esophageal-genomic-subtypes New Molecular Classification of Gastroesophageal Cancers REGARD Trial Previously treated gastric or GEJ adenocarcinoma N = 355 Stratification factors: Region Weight loss ( 10% vs <10% over 3 months) Location of primary tumor (gastric vs GEJ) R A N D O M I Z E 2:1 Ramucirumab 8 mg/kg q2wk + BSC (n = 238) Placebo q2wk + BSC (n = 117) Multicenter, randomized, double-blind, placebo-controlled, phase III trial Primary endpoint: OS ESCC esophageal squamous cell; CIN - chromosomal instability; GS = genomically stable Fuchs CS et al. Lancet REGARD Trial Primary Endpoint Ramucirumab Placebo Patients/events 238 / / 99 Median OS, months (95% CI) 5.2 ( ) 3.8 ( ) 6-month OS 42% 32% 12-month OS 18% 11% HR = (95% CI, ) Log rank (stratified) P= REGARD Trial Adverse events Ramucirumab (n = 236) Placebo (n = 115) Any Grade Grade 3 Any Grade Grade 3 (%) (%) (%) (%) Hypertension Bleeding/Hemorrhage Arteriothromboembolic Venous thromboembolic Proteinuria 3 <1 <1 <1 GI perforation <1 <1 <1 <1 Fistula (GI and non-gi) <1 <1 <1 <1 Infusion-related reaction < Cardiac failure < Fuchs CS et al. Lancet Fuchs CS et al. Lancet RAINBOW Trial N=665 Metastatic or locally advanced unresectable gastric or GEJ adenocarcinoma Progression after first-line platinum/fluoropyrimidinebased chemotherapy R A N D O M I Z E Ramucirumab 8 mg/kg on days 1 and 15 + paclitaxel 80 mg/m 2 on days 1, 8, and 15 of 28-day cycle n = 330 Placebo on days 1 and 15 + paclitaxel 80 mg/m 2 on days 1, 8, and 15 n = 335 Randomized, placebo-controlled, double-blind phase III trial Stratification factors Geographic region Measurable vs non-measurable disease Time to progression on first-line therapy (<6 mos vs 6 mos Primary endpoint: OS RAINBOW Trial Overall Survival No. at risk Ramucirumab + Paclitaxel Median (mos) (95% CI) 9.63 ( ) Δ RAM mos + = 2.3 PTXmonth Months Placebo + Paclitaxel 7.36 ( ) 6-month OS 72% 57% 12-month OS 40% 30% PBO + PTX RAM - Ramucirumab; PTX - Paclitaxel; PBO - Placebo HR = (95% CI, ) Stratified log rank P= Wilke H et al. Lancet Oncol Wilke H et al. Lancet Oncol

7 RAINFALL Trial Randomized, Phase III, first-line study in patients with metastatic gastric or gastroesophageal junction adenocarcinoma N=21 HER2- Cisplatin + capecitabine or 5-FU + ramucirumab Primary endpoint: PFS Secondary endpoint: OS Median PFS 5.7 months vs. 5.4 months (HR 0.75, 95% CI , p=0.0024) Median OS months vs months NS Increase in ramucirumab-related adverse events Second-line or Subsequent Therapy Based on prior therapy and performance status Preferred regimens Ramucirumab + paclitaxel (category 1) Docetaxel (category 1) Paclitaxel (category 1) Irinotecan (category 1) 5-FU + irinotecan Pembrolizumab MSI-H or dmrr tumors Other recommended regimens Ramucirumab (category 1) Irinotecan + cisplatin Pembrolizumab Third-line or subsequent for PD-L1 positive adenocarcinoma Docetaxel + irinotecan Fuchs CS et al. J Clin Oncol. 2018;36(suppl 4): abstract 5. Checkpoint Immunotherapy Pembrolizumab Approved for second line or subsequent use in MSI-H or dmrr tumors KEYNOTE-016 Phase II with dmmr non-colorectal arm (at least two prior therapies) N=9 KEYNOTE-012 Recurrent or metastatic adenocarcinoma of stomach or GEJ ECOG PS 0 1 PD-L1 + tumor No systemic steroid therapy No autoimmune disease (active or history of) No active brain metastases Pembrolizumab 10 mg/kg Q2W Immune-related Median PFS Median OS Grade 3-4 Treatment Arm Overall Response (months) (months) Adverse Events Rate (ORR) Pembrolizumab 10mg/kg 71% 5.4 NR 41% IV Q 2 weeks Adverse events Pruritus, hypothyroidism, asymptomatic pancreatitis, anemia Phase 1b multicenter, open-label trial Only patients with PD-L1 staining in stroma or in 1% of tumor cells were eligible for enrollment 65 of 162 (40%) patients assessed for PD-L1 expression had PD-L1+ tumors Trial endpoints: Overall response rate and safety LE DT J et al. N Eng J Med Muro K et al. Lancet Oncol KEYNOTE-012 Response with Pembrolizumab Central Review Investigator Review n = 36 n = 39 ORR, % (95% CI) 22.2 ( ) 33.3 ( ) Best overall response, n (%) Complete response 0 0 Partial response 8 (22.2) 13 (33.3) Stable response 5 (13.9) 5 (12.8) Progressive disease 19 (52.8) 21 (53.8) No assessment 1 (2.8) Not determined 3 (8.3) KEYNOTE-012: Adverse events of interest Event, n (%) Grade 1 2 Grade 3-4 Any 7 (17.9) 2 (5.2) Hypothyroidism 4 (10.3) 1 (2.6) Hyperthyroidism 3 (7.7) 0 (0.0) Pneumonitis 1 (2.6) 1 (2.6) Colitis 1 (2.6) 0 (0.0) Hepatitis 1 (2.6) 0 (0.0) Thyroiditis 1 (2.6) 0 (0.0) Muro K et al. Lancet Oncol AE = adverse event. Muro K et al. Lancet Oncol

8 KEYNOTE-059 COHORT 1 PD-L1 + or PD-L1 Prior systemic therapies N = 180 Pembrolizumab 200 mg Q3W COHORT 2 PD-L1 + or PD-L1 No prior systemic therapy N = 40 Pembrolizumab 200 mg + cisplatin + 5-FU, all Q3W COHORT 3 PD-L1 + only No prior systemic therapy N=50 Pembrolizumab 200 mg Q3W Phase II trial Cohort 1 - advanced gastric or GEJ adenocarcinoma progressed on two or more lines of therapy A specimen is considered to have positive PD-L1 expression if combined positive score (CPS) 1% Primary endpoint: ORR Cohorts 2 and 3 enrollment is ongoing Muro K et al. J Clin Oncol. 2015;33(suppl 3): abstract 3. KEYNOTE-059 Cohort 1 ORR for all patients 11.6% Response PD-L1 Positive (n = 148) Median duration of response 16.3 months PD-L1+ vs. 6.9 months PD-L1- PD-L1 Negative (n = 109) % 95% CI % 95% CI ORR (CR + PR) CR PR DCR DCR = CR + PR + SD 2 months Fuchs CS et al. J Clin Oncol. 2017;35(suppl): abstract CheckMate-032 Nivolumab 3 mg/kg IV every 2 weeks R Metastatic or locally n = 59 advanced chemotherapy A refractory gastric, esophageal N or GEJ cancer D Nivolumab 1mg/mkg IV N=160 O Ipilimumab 3 mg/kg IV every 3 weeks M n = 49 ECOG 0 or 1 I HER2 + if received Z trastuzumab Nivolumab 3 mg/mkg IV E Ipilimumab 1 mg/kg IV every 3 weeks n = 52 Open-label, two-stage multicohort, phase I/II trial PD-L1 status assessed Primary endpoint: ORR CheckMate-032 Nivolumab 3 mg/kg Nivolumab 1 mg/kg Ipilimumab 3 mg/kg Nivolumab 3 mg/kg Ipilimumab 1 mg/kg ORR 12% (95% CI 5-23%) 24% (95% CI 13-39%) 8% (95% CI 2-19%) 12-month PFS 8% 17% 10% 12-month OS 39% 35% 24% Grade 3/4 17% 47% 27% adverse events Response observed regardless of PD-L1 status Adverse events Most common Fatigue, rash, pruritus, diarrhea, decrease appetite, increased AST/ALT Janjigian YY et al. J Clin Oncol Janjigian YY et al. J Clin Oncol Best Supportive Care Goal To prevent, reduce and relieve suffering Improve quality of life Common symptoms Dysphagia Alternate route for medications Obstruction Alternate route for medications Bleeding Anemia management ph altering medications Pain Nausea/vomiting Summary The treatment of esophagogastric cancer requires a multidisciplinary approach and pharmacists play an important part Preoperative chemoradiation has been shown to improve survival in locoregional esophagogastric cancer Increased molecular understanding of esophagogastric cancers has lead to the development of targeted and immunotherapy treatment options Appropriate monitoring and management of drug- and treatmentrelated toxicities are key for optimal patient outcomes Continued research in these cancers is necessary to provide better understanding of current and future therapeutic options 8